title: Role of electron microscopy in the diagnosis of cadasil syndrome: a study of 32 patients.
abstract: OBJECTIVE
  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 gene mutations that result in vascular smooth muscle cell (VSMC) degeneration. Its distinctive feature by electron microscopy (EM) is granular osmiophilic material (GOM) detected in VSMC indentations and/or the extracellular space close to VSMCs. Reports of the sensitivity of EM in detecting GOM in biopsies from CADASIL patients are contradictory. We present data from 32 patients clinically suspected to have CADASIL and discuss the role of EM in its diagnosis in this retrospective study.
  
  
  METHODS
  Skin, skeletal muscle, kidney and pericardial biopsies were examined by EM; the NOTCH3 gene was screened for mutations. Skin and muscle biopsies from 12 patients without neurological symptoms served as controls.
  
  
  CONCLUSIONS
  All GOM-positive patients exhibited NOTCH3 mutations and vice versa. This study i) confirms that EM is highly specific and sensitive for CADASIL diagnosis; ii) extends our knowledge of GOM distribution in tissues where it has never been described, e.g. pericardium; iii) documents a novel NOTCH3 mutation in exon 3; and iv) shows that EM analysis is critical to highlight the need for comprehensive NOTCH3 analysis. Our findings also confirm the genetic heterogeneity of CADASIL in a small Italian subpopulation and emphasize the difficulties in designing algorithms for molecular diagnosis.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy, School of Medicine, Università Politecnica delle Marche, Ancona, Italy. m.morroni@univpm.it
authors.forename: Manrico
authors.initials: M
authors.lastname: Morroni
authors.forename: Daniela
authors.initials: D
authors.lastname: Marzioni
authors.forename: Michele
authors.initials: M
authors.lastname: Ragno
authors.forename: Paolo
authors.initials: P
authors.lastname: Di Bella
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cartechini
authors.forename: Luigi
authors.initials: L
authors.lastname: Pianese
authors.forename: Teresa
authors.initials: T
authors.lastname: Lorenzi
authors.forename: Mario
authors.initials: M
authors.lastname: Castellucci
authors.forename: Marina
authors.initials: M
authors.lastname: Scarpelli
mesh_terms: D000328:Adult; D001706:Biopsy; D046589:CADASIL / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008854:Microscopy, Electron / Q000379:methods*; D008875:Middle Aged; D009154:Mutation; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D012680:Sensitivity and Specificity
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch